The mucosal barrier of the upper gastrointestinal tract is a composite property of the lumenal membranes of the epithelial cells and the junctional complexes between these cells. We have characterized the barrier of the gastric fundus of the amphibian Necturus. In the fundus the paracellular conductance (between the cells) is 1/5 of the cellular conductance (through the cell). In the antrum the paracellular conductance is 3 times the cellular conductance; thus confirming findings of diffusional losses from canine pouches. The antrum is therefore a "leaky" tissue while the fundus is "tight". In the proposed research we will examine this concept in mammalian gastric fundus, antrum and duodenum. This barrier function will be characterized in terms of the cellular and paracellular conductance of each area (fundus, antrum and duodenum). In addition the barrier function of these regions will be defined in terms of permeability to molecules of varying molecular weight and also in terms of effective pore size. The change in the barrier as defined by these parameters will be assessed after treatment of the mucosa with various agents known to cause gastric mucosal injury (ASA, phenylbutazone, indomethacin, cincophen, hydrocortisone, bile salts, alcohol). The mechanism of injury to the gastric mucosal barrier will be assessed by studying the effect of these agents on O2 consumption and ATP content of intact mucosa and isolated gastric cells. In addition the effect of these agents on gastric mitochondrial metabolism will be assessed.